Cephalosporins Antibiotics

Cephalosporins Antibiotics

Cephalosporins Antibiotics

The bactericidal cephalosporins are broad-spectrum antibacterials, with the same mode of action as the penicillins. They are categorised into ‘generations’ depending on their spectrum of activity.

The cephalosporins received their name from the fungus Cephalosporium acremonium, which was the source of the first members of this class. Even more so than penicillins, these agents constitute a large extended family of antibiotics within the β-lactam group. As such, they are appropriately categorized by “generation.” Since agents in each generation have somewhat similar spectra of activity, this organizational scheme is helpful in remembering the properties of the many cephalosporins.

Each cephalosporin is composed of a nucleus with two side chains. The nucleus is 7-aminocephalosporanic acid, which is similar to the nucleus of penicillin except that the β-lactam ring is fused to a six-member dihydrothiazine ring instead of a five-member thiazolidine ring. The cephalosporin core has two major advantages over the penicillin core: (1) It is intrinsically more resistant to cleavage by β-lactamases and (2) it has two sites, at which it can be modified. This in part explains the large number of cephalosporins commercially available today.

Like other β-lactam antibiotics, the cephalosporins exert their effects by attaching to and inhibiting PBPs, thereby preventing the appropriate synthesis of peptidoglycan.

Mechanism of resistance

Although peptidoglycan is a constituent of most bacteria, cephalosporins are not active against certain species and strains of bacteria. As was the case for penicillins, the six Ps explain resistance to cephalosporins:

Penetration—cephalosporins, like most β-lactams, penetrate poorly into the intracellular compartment of human cells, so bacteria that for the most part reside in this compartment, such as Rickettsia and Legionella, are protected from them.

Porins—some gram-negative bacteria, such as P. aeruginosa, have porins in their outer membranes that do not allow passage of many cephalosporins into the periplasmic space.

Pumps—some bacteria, such as P. aeruginosa, use effl ux pumps to remove antibiotics from the periplasmic space.

Penicillinases (actually β-lactamases)—many gram-negative bacteria, such as Enterobacter and Citrobacter spp., make β-lactamases that degrade many cephalosporins.

PBPs—some bacteria, such as the enterococci and Listeria monocytogenes, produce PBPs that do not bind most cephalosporins with a high affi nity.

Peptidoglycan—some bacteria such as Mycoplasma and Chlamydia do not make peptidoglycan and therefore are not affected by the cephalosporins.

Several generalizations about the spectra of activity of cephalosporins can be made. First, with the exception of the new fi fth-generation agents, each successive generation of agents has broader activity against aerobic gram-negative bacteria. Second, also with several important exceptions, cephalosporins have limited activity against anaerobes. Third, the activities of these agents against aerobic gram-positive bacteria are variable, with the fi fth-generation agent ceftaroline having the strongest activity against these bacteria.

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FIRST-GENERATION CEPHALOSPORINS

Commonly used first-generation cephalosporins include cefadroxil and cefazolin. All agents in this group share similar activities against the different typesof bacteria.

The strength of the first-generation cephalosporins is their activity against aerobic gram-positive cocci such as staphylococci and streptococci. The first side chains of these agents protect their β-lactam rings from cleavage by the staphylococcal β-lactamase. As a result, they are useful in the treatment of infections caused by many strains of Staphylococcus aureus. First-generation cephalosporin cannot bind the PBPs of MRSA and MRSE or many highly penicillin-resistant Streptococcus pneumoniae; these agents are ineffective against these bacteria. As mentioned previously, most cephalosporins also lack activity against L. monocytogenes and the enterococci.

First-generation cephalosporins have limited activity against aerobic and facultative gram-negative bacteria, primarily because the side chains of these agents, although capable of protecting the β-lactam ring from cleavage by staphylococcal β-lactamases, do not afford protection from the β-lactamases of most gram-negative bacteria. Nonetheless, some strains of E. coli, Klebsiella pneumoniae, and P. mirabilis are susceptible. First-generation cephalosporins have moderate to poor activity against anaerobes, intracellular bacteria, and spirochetes.

Antimicrobial Activity of First- Generation Cephalosporins

Gram-positive bacteria

  • Streptococcus pyogenes
  • Some viridans streptococci
  • Some Staphylococcus aureus
  • Some Streptococcus pneumoniae

Gram-negative bacteria

  • Some Escherichia coli
  • Some Klebsiella pneumoniae
  • Some Proteus mirabilis

SECOND-GENERATION CEPHALOSPORINS

Second-generation cephalosporins are divided into two groups: the true cephalosporins, such as cefuroxime, and the cephamycins, which include cefotetan and cefoxitin. The cephamycins are derivatives of a parent compound originally isolated from the bacterium Streptomyces lactamdurans instead of the fungus C. acremonium.

They have a methoxy group in place of the hydrogen on the β-lactam ring of the cephalosporin core. Thus, these agents are not actually cephalosporins but are included in this group because they are chemically and pharmacologically similar.

Individual second-generation cephalosporins differ in their activity against aerobic gram-positive bacteria. The true cephalosporins are in general as active against aerobic gram-positive cocci as the fi rst-generation agents. The cephamycins (cefotetan and cefoxitin) have relatively limited activity against this group of bacteria.

The strength of the second-generation agents is their increased activity against aerobic and facultative gram-negative bacteria. Second-generation agents are more potent against E. coli, K. pneumoniae, and P. mirabilis than fi rst-generation agents and are also active against Neisseria spp. and, in the case of the true cephalosporins, H. infl uenzae (including β-lactamase-producing strains). Because of the additional methoxy group on the β-lactam ring, the cephamycins also have enhanced stability to the β-lactamases of some anaerobes, such as B. fragilis. However, this added anaerobic activity comes at a cost; it is the methoxy group that results in the diminished activity of the cephamycins against staphylococci and streptococci because of decreased affi nity for the PBPs of these bacteria.

Antimicrobial Activity of Second-Generation Cephalosporins

Gram-positive bacteria

  • True cephalosporins have activity equivalent to first-generation agents Cefoxitin and cefotetan have little activity

Gram-negative bacteria

  • Escherichia coli
  • Klebsiella pneumoniae
  • Proteus mirabilis
  • Haemophilus infl uenzae
  • Neisseria spp.

Anaerobic bacteria

  • Cefoxitin and cefotetan have moderate anaerobic activity
THIRD-GENERATION CEPHALOSPORINS

Commonly used third-generation cephalosporins include ceftriaxone, cefotaxime, and ceftazidime. In general, compounds in this group have moderate activity against aerobic gram-positive bacteria and inhibit most strains of penicillin-susceptible S. pneumoniae. Third-generation cephalosporins are also active against the spirochete Borrelia burgdorferi but have little activity against anaerobic bacteria.

A modifi cation common to many of the third-generation cephalosporins is the use of an aminothiazolyl group at first side chain site. The presence of this structure at the first side chain site results in increased penetration of these agents through the bacterial outer membrane, increased affi nity for PBPs, and increased stability in the presence of some of the plasmid-encoded β-lactamases of aerobic and facultative gram-negative bacteria.

Thus, these agents have enhanced activity against E. coli, Klebsiella spp., Proteus spp., Neisseria spp., and H. infl uenzae relative to the second-generation cephalosporins. In addition, many other strains of the Enterobacteriaceae, including Enterobacter spp., Citrobacter freundii, Providencia spp., Morganella morganii, and Serratia spp., also initially show susceptibility to third-generation cephalosporins. However, these bacteria harbor chromosomally encoded inducible AmpC β-lactamases that may allow the emergence of resistance during treatment. Thus, it is now felt that infections caused by these organisms should either not be treated with third-generation cephalosporins or should be treated with these agents in conjunction with a second active agent, even if they appear to be susceptible by in vitro testing.

One shortcoming of most of the third-generation cephalosporins is their lack of activity against P. aeruginosa. To address this, the aminothiazolyl the first side chain side chain of ceftazidime was modifi ed by the addition of a carboxypropyl group, which dramatically increases antipseudomonal activity. Unfortunately, this modifi cation also results in decreased affi nity for the PBPs of staphylococci. As a result, ceftazidime has enhanced activity against P. aeruginosa but limited activity against S. aureus.

Among the third-generation cephalosporins, ceftriaxone is notable for its long half-life. This agent is widely used because of the convenience of its once per day dosing.

Antimicrobial Activity of Third-Generation Cephalosporins
  • Gram-positive bacteria
  • Streptococcus pyogenes
  • Viridans streptococci
  • Many Streptococcus pneumoniae
  • Modest activity against Staphylococcus aureus

Gram-negative bacteria

  • Escherichia coli
  • Klebsiella pneumoniae
  • Proteus spp.
  • Haemophilus infl uenzae
  • Neisseria spp.
  • Some Enterobacteriaceae

Spirochetes

  • Borrelia burgdorferi
FOURTH-GENERATION CEPHALOSPORINS

As mentioned earlier, the third-generation cephalosporins are powerful antimicrobial agents but suffer from susceptibility to the chromosomally encoded inducible AmpC β-lactamases of many of the Enterobacteriaceae. In addition, activity against P. aeruginosa is gained only at the expense of diminished antistaphylococcal activity. Attempts to address these deficiencies led to modifi cations of the second side chain of the thirdgeneration cephalosporins while leaving the highly successful aminothiazolyl group at first side chain unchanged. The result of these efforts was the fourth-generation cephalosporin cefepime. The side chains of cefepime allow more rapid penetration through the outer membrane of many gram-negative bacteria, including P. aeruginosa.

It also binds at a high affi nity to many of the PBPs of these bacteria but is relatively resistant to hydrolysis by gram-negative β-lactamases, including the chromosomally encoded inducible AmpC β-lactamases of the Enterobacteriaceae (although the clinical relevance of this is controversial). These properties are attained without the loss of activity against aerobic gram-positive cocci. Thus, this incredibly powerful antibiotic has the best features of the various third-generation cephalosporins (antipseudomonal activity without loss of antistaphylococcal activity) and may also have enhanced activity against many of the Enterobacteriaceae. Cefepime has very limited anaerobic activity.

Antimicrobial Activity of Fourth-Generation Cephalosporins

Gram-positive bacteria

  • Streptococcus pyogenes
  • Viridans streptococci
  • Many Streptococcus pneumoniae
  • Modest activity against Staphylococcus aureus

Gram-negative bacteria

  • Escherichia coli
  • Klebsiella pneumoniae
  • Proteus spp.
  • Haemophilus infl uenzae
  • Neisseria spp.
  • Many other Enterobacteriaceae
  • Pseudomonas aeruginosa
FIFTH-GENERATION CEPHALOSPORINS

Ceftaroline is a new cephalosporin that has expanded activity against aerobic gram-positive cocci, causing some experts to refer to it as a fifth-generation agent. A 1,3-thiazole ring has been added to the SECOND  side chain of this cephalosporin, which confers upon it the ability to bind to the PBP of methicillin-resistant staphylococci. As a result, ceftaroline has excellent activity against aerobic gram- positive cocci, including methicillin-resistant Staphylococcus aureus

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and Staphylococcus epidermidis and penicillin-resistant Streptococcus pneumoniae strains. Its activities against aerobic gram-negative bacteria are similar to that of cefotaxime and ceftriaxone; it lacks antipseudomonal activity. Ceftaroline also has activity against anaerobic gram-positive bacteria but not against anaerobic gram-negative bacteria. This agent is administered as the inactive prodrug ceftaroline fosamil, which is rapidly converted to ceftaroline.

Antimicrobial Activity of Fifth-Generation Cephalosporins

Gram-positive bacteria

  • Streptococcus pyogenes
  • Viridans streptococci
  • Streptococcus pneumoniae
  • Staphylococci

Gram-negative bacteria

  • Escherichia coli
  • Klebsiella pneumoniae
  • Proteus spp.
  • Haemophilus infl uenzae
  • Neisseria spp.
  • Some Enterobacteriaceae

Anaerobic bacteria

  • Some Clostridium spp.
KEY POINTS
  • First generation’ cephalosporins are useful in treating urinary tract infections, skin and soft tissue infections, and respiratory tract infections. One example is cefalexin, an oral agent which has good activity against Gram-positive bacteria such as Staphylococcus aureus, Staphylococcus pneumoniae and Staphylococcus pyogenes. All methicillin-resistant Staphylococcus aureus (MRSA) strains are resistant.
  • ‘Second generation’ cephalosporins have increased activity against Gram-negative bacteria. Cefuroxime, for example, is mainly used in surgical prophylaxis.
  • ‘Third generation’ cephalosporins have good broad-spectrum activity. Cefotaxime and ceftriaxone, for example, have good broad-spectrum activity against Gram-
    negative and Gram-positive bacteria. They are often used in empirical therapy for meningitis and pneumonia. Ceftazidime has excellent activity against pseudomonal infection. They are increasingly linked with causing Clostridium difficile infections in hospital and community medical institutions.
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